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Harvard Commentaries
Harvard Commentaries
Reviewed by the Faculty of Harvard Medical School

Minding Your Mind Minding Your Mind

Nocebo -- The Dark Side of the Placebo Effect

January 28, 2014

By Michael Craig Miller M.D.

Harvard Medical School

A "nocebo" is the flip side of the much better known placebo response. It could be considered the dark side of the placebo effect.

In Latin, nocebo means "I will harm," while placebo means "I will please." A placebo can enhance healing or pain relief, while a nocebo has the opposite effect — it makes patients feel worse.

Here's a closer look at the nocebo response.

Placebos and Side Effects

All drugs cause adverse effects. It turns out that people experience unwanted effects with placebo pills too.

This puzzles researchers, because placebo pills are usually made of sugar or some other inert substance. Theoretically they should have no biological effect. Even more intriguing, research suggests that the type of side effect a placebo causes will vary depending on the active drug being tested.

Consider randomized clinical trials comparing different classes of migraine drugs with placebos. Such trials are usually "blinded," meaning neither the researchers nor the participants know who is receiving the placebo.

In studies that test the effects of nonsteroidal anti-inflammatory drugs (NSAIDs), patients assigned to the placebo group report nausea, vomiting and other gastrointestinal problems. These are all side effects that can occur after taking NSAIDs.

Antiseizure drugs are also used to treat migraine. In studies assessing these drugs, patients taking a placebo report loss of appetite, memory problems and upper respiratory infections. These are all side effects of anticonvulsants.

This phenomenon is not just observed in studies of migraine medication. In placebo controlled trials, patients who are taking the placebo often report uncomfortable side effects that are characteristic of the active drugs being studied.

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Theories about the Nocebo Effect

As with the placebo response, several factors may contribute to the nocebo response.

  • State of mind. Anxiety, depression and preoccupation with physical symptoms or illness increase susceptibility to the nocebo response. It's not clear why, but one theory is that these psychological states may cause people to express emotional disturbances in the form of physical symptoms.
  • Conditioning. When patients have had a negative experience or developed side effects in the past, they may do so again in response to sights, sounds or other cues associated with that treatment. For example, as many as one in three patients become nauseated or even vomit on entering a room where they have recently received chemotherapy.
  • Context. Red, orange and yellow are colors associated with stimulation, while blue and green suggest sedation. Studies have found that participants who take blue placebo pills are more likely to say they feel drowsy afterward than people who take pink placebos.
  • Suggestion. The words a clinician uses to describe possible side effects of treatment — or even the forms used to provide informed consent — can create expectations of outcomes. In one placebo-controlled study of aspirin for chest pain, researchers used two variations of a consent form. One specifically listed "gastrointestinal irritation" as a possible side effect, while the other did not. In the placebo group, patients who had signed the consent form listing gastrointestinal irritation not only were more likely to experience this distress, but were also more likely to drop out of the study as a result.

Other research in healthy subjects has shown that the use of certain words — such as experimenters who warn that a mild electric shock might hurt a great deal — increases participants' own rating of pain severity.

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Unanswered Questions

The biology of the nocebo response remains largely unknown. The placebo response activates endorphins in the brain to provide pain relief. Some researchers suggest that a nocebo may activate other receptors that stimulate the production of stress hormones, like cortisol, and affect perception of pain in other ways. Benzodiazepines, drugs used to treat anxiety, can blunt the nocebo effect on pain. This suggests that the brain changes that contribute to anxiety may also underlie the nocebo response.

Although many questions remain about the mechanisms, the existence of the nocebo effect is an important reminder of the need to consider the context in which treatment takes place. Clinicians are wise to establish trust and address a patient's concerns about treatment in a positive way whenever possible. As research continues, the hope is that clinicians will have better guidance about how to invoke the placebo response — and avoid invoking the nocebo response. This can help ensure that patients have every chance to heal and relieve pain.

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Michael Craig Miller, M.D. is the former editor-in-chief of the Harvard Mental Health Letter and an assistant professor of psychiatry at Harvard Medical School. Dr. Miller has an active clinical practice and has been on staff at Beth Israel Deaconess Medical Center for more than 30 years.

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